Protein Stability, Folding and Misfolding in Human PGK1 Deficiency
Abstract
:1. Introduction
2. Human PGK1 Deficiency
2.1. Clinical Presentation and Current Treatments
2.2. Genetics and Genotype/Phenotype Correlations in hPGK1 Deficiency
3. Functional and Stability Defects in Human PGK1 Deficiency
3.1. Overview of Human PGK1 Structure and Activity
3.2. Structural and Functional Impact of Mutations in the Native hPGK1
Nucleotide Change | Amino Acid Change | a Localization | b Catalytic Properties | c Protein Stability | RBC Residual Activity (%) | Hb (g/dl) | Reticulocytes (%) | d Symptoms | References | ||
---|---|---|---|---|---|---|---|---|---|---|---|
A | M | N | |||||||||
c.140 T > A | # p.I47N | α-helix 1b | ○ | ○○○ | 8 | 6.6–7.3 | N.A. | + | - | + | [37] |
c.266 T > C | # p.L89P | α-helix 2 * | ○ | ○○○ | 5 | N.A. | N.A. | + | - | + | [40] |
c.473 G > T | # p.G158V | loop α-helix 4, β-strand E | ○○ | ○○ | 1 | 12.8 | 2.5 | - | + | - | [65] |
c.491 A > T | # p.D164V | β-strand E | ○○○ | ○○○ | 5 | 2.0–10.0 | 5.0-26-0 | + | +/- | + | [36,38,41,66] |
c.571 > 573 del | # p.K191del | α-helix 7 * | ○○ | ○○ | 4 | 14.1 | 6.4 | - | - | - | [41] |
c.617 G > C | # p.R206P | loop α-helix 7, β-strand G * | - | ○ | 10 | 5.6–13.7 | 2.0–20.0 | +/- | - | + | [67] |
c.755 A > C | # p.E252A | loop α-helix 9, α-helix 10 * | - | - | 6 | 13.2 | N.A. | - | + | - | [68] |
c.758 T > C | # p.I253T | loop α-helix 9, α-helix 10 * | - | - | 8 | N.A. | N.A. | - | + | + | [69] |
c.796 G > A c.798 C > A | # p.V266M | α-helix 10a/b | - | - | 10 | 9.3 | 12.5 | + | - | + | [70] |
c.802 G > A | # p.D268N | α-helix 10b * | - | - | 21 | N.A. | 0.4–1.3 | - | - | - | [71] |
c.854 A > T | # p.D285V | β-strand o * | ○○ | ○○○ | 49 | 9.0–10.0 | 10–45 | - | - | - | [68] |
c.943 G > A | # p.D315N | β-strand q | ○○ | ○○○ | 3 | 14.3 | N.A. | - | + | - | [72] |
c.946 T > C | # p.C316R | β-strand q | ○ | ○○○ | 10 | 7.5-13.0 | 1.5–5.0 | +/- | - | + | [66] |
c.959 G > A | # p.S320N | α-helix 11 | ○ | ○○○ | 36 | 7.6 | 9.0 | + | - | + | [73] |
c.1060 G > C | # p.A354P | α-helix 12 * | ○ | ○○○ | 6 | 4.9–9.0 | 24 | + | + | + | [37] |
c.1112 T > A | # p.I371K | β-strand K | ○○ | ○○ | 12 | 12.1–14.1 | 4.4–5.2 | +/- | + | + | [30] |
c.1132 A > C | # p.T378P | α-helix 13 * | ○○ | - | 2 | 13.4–14.5 | N.A. | - | + | - | [28,29] |
IVS4+1 G > T | splicing alteration | 3 | N.A. | 2.7 | - | + | + | [74] | |||
c.637 > 640 delGGCG | frameshift | 6 | N.A. | N.A. | - | + | - | [75] | |||
c.639 C > T | splicing alteration | 5 | N.A. | N.A. | - | + | - | [76,77] | |||
IVS7+5 G > A | splicing alteration | 14 | N.A. | N.A. | - | + | + | [78] |
3.3. Increased Aggregation Propensity of Mutants Causing hPGK1 Deficiency: Biophysical and Expression Studies
3.4. Structural and Energetic Bases of Mutation Induced Kinetic Destabilization of hPGK1
Chemical Denaturation | WT | p.T378P |
---|---|---|
Cm (M) | 2.43 ± 0.01 | 2.28 ± 0.06 |
meq (kcal·mol−1·M−1) | 3.4 ± 0.2 | 1.5 ± 0.2 |
ΔGU (kcal·mol−1) | 8.3 ± 0.5 | 3.5 ± 0.4 |
Thermal denaturation | ||
Tm (°C) | 52.8 ± 0.2 | 49.8 ± 0.4 |
Ea (kcal·mol−1) | 191 ± 19 | 135 ± 12 |
ΔH (kcal·mol−1) | 157 ± 18 | 127 ± 9 |
Kinetic stability | ||
Aggregation rate constant (kagg)(min−1) | 9 ± 5·10−7 | 1.6 ± 0.4·10−4 |
Global unfolding rate constant (kunf(0M)) (min−1) | 0.09 ± 0.02 | 0.18 ± 0.04 |
Proteolysis rate constant at high protease (k0) (min−1) | 0.11 ± 0.02 | 0.38 ± 0.01 |
Proteolysis rate constant at low protease (k1) (min−1) | 0.27 ± 0.04 | 7.8 ± 0.5 |
3.5. Dissection of the Thermodynamic and Kinetic Basis of hPGK1 Misfolding by Urea Denaturation and Proteolysis
3.6. A Possible Role of Folding/Unfolding Cooperativity in the Loss-of-Function Mechanisms of hPGK1 Deficiency
3.7. hPGK1 Mutants may affect Spontaneous Refolding Kinetics
3.8. Folding, Stability and Function of PGK inside the Cell
4. Perspectives for Pharmacological Intervention in hPGK1 Deficiency
Acknowledgments
Conflicts of Interest
References
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Valentini, G.; Maggi, M.; Pey, A.L. Protein Stability, Folding and Misfolding in Human PGK1 Deficiency. Biomolecules 2013, 3, 1030-1052. https://doi.org/10.3390/biom3041030
Valentini G, Maggi M, Pey AL. Protein Stability, Folding and Misfolding in Human PGK1 Deficiency. Biomolecules. 2013; 3(4):1030-1052. https://doi.org/10.3390/biom3041030
Chicago/Turabian StyleValentini, Giovanna, Maristella Maggi, and Angel L. Pey. 2013. "Protein Stability, Folding and Misfolding in Human PGK1 Deficiency" Biomolecules 3, no. 4: 1030-1052. https://doi.org/10.3390/biom3041030